ArticleProceedings of the National Academy of Sciences of the United States of America2010
Specific insertions of zinc finger domains into Gag-Pol yield engineered retroviral vectors with selective integration properties.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed.
- Engineered virus-like particles for transient delivery of prime editor ribonucleoprotein complexes in vivo.Nature biotechnology · 2024Article
- Cellular Response of Ventricular-Subventricular Neural Progenitor/Stem Cells to Neonatal Hypoxic-Ischemic Brain Injury and Their Enhanced Neurogenesis.Yonsei medical journal · 2020Article
- Shifting Retroviral Vector Integrations Away from Transcriptional Start Sites via DNA-Binding Protein Domain Insertion into Integrase.Molecular therapy. Methods & clinical development · 2019Article
- Synthetic biology advances and applications in the biotechnology industry: a perspective.Journal of industrial microbiology & biotechnology · 2018Article
- Article
- Stability of Retroviral Vectors Against Ultracentrifugation Is Determined by the Viral Internal Core and Envelope Proteins Used for Pseudotyping.Molecules and cells · 2017Article
- Recent advances in developing molecular tools for targeted genome engineering of mammalian cells.BMB reports · 2015Review
- Efficient Transduction of LEDGF/p75 Mutant Cells by Gain-of-Function HIV-1 Integrase Mutant Viruses.Molecular therapy. Methods & clinical development · 2014Article
- Advances in homology directed genetic engineering of human pluripotent and adult stem cells.World journal of stem cells · 2013Article
- Engineering a serum-resistant and thermostable vesicular stomatitis virus G glycoprotein for pseudotyping retroviral and lentiviral vectors.Gene therapy · 2013Article
- Astrocytes regulate adult hippocampal neurogenesis through ephrin-B signaling.Nature neuroscience · 2012Article
- Retroviral infection of hES cells produces random-like integration patterns.Molecules and cells · 2012Article
- Antiviral RNAi: translating science towards therapeutic success.Pharmaceutical research · 2011Review
- From DNA to targeted therapeutics: bringing synthetic biology to the clinic.Science translational medicine · 2011Review
- Targeted plasmid integration into the human genome by an engineered zinc-finger recombinase.Nucleic acids research · 2011Article
- Ex vivo gene therapy for HIV-1 treatment.Human molecular genetics · 2011Review
- Genetic therapies for cystic fibrosis lung disease.Human molecular genetics · 2011Review
- An evolved adeno-associated viral variant enhances gene delivery and gene targeting in neural stem cells.Molecular therapy : the journal of the American Society of Gene Therapy · 2011Article
- The mechanism of retroviral integration from X-ray structures of its key intermediates.Nature · 2010Article
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Authors and funding
4 authors.
Funding
Abstract
Retroviral vectors offer benefits of efficient delivery and stable gene expression; however, their clinical use raises the concerns of insertional mutagenesis and potential oncogenesis due to genomic integration preferences in transcriptional start sites (TSS). We have shifted the integration preferences of retroviral vectors by generating a library of viral variants with a DNA-binding domain inserted at random positions throughout murine leukemia virus Gag-Pol, then selecting for variants that are viable and exhibit altered integration properties. We found seven permissive zinc finger domain (ZFD) insertion sites throughout Gag-Pol, including within p12, reverse transcriptase, and integrase. Comprehensive genome integration analysis showed that several ZFD insertions yielded retroviral vector variants with shifted integration patterns that did not favor TSS. Furthermore, integration site analysis revealed selective integration for numerous mutants. For example, two retroviral variants with a given ZFD at appropriate positions in Gag-Pol strikingly integrated primarily into four common sites out of 3.1 x 10(9) possible human genome locations (P = 4.6 x 10(-29)). Our findings demonstrate that insertion of DNA-binding motifs into multiple locations in Gag-Pol can make considerable progress toward engineering safer retroviral vectors that integrate into a significantly narrowed pool of sites on human genome and overcome the preference for TSS.
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